US7645738B2 - 18-membered nitrobenzyl- and aminobenzyl-substituted cyclohexadepsipeptides for controlling endoparasites and a process for their preparation - Google Patents

18-membered nitrobenzyl- and aminobenzyl-substituted cyclohexadepsipeptides for controlling endoparasites and a process for their preparation Download PDF

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US7645738B2
US7645738B2 US10/582,555 US58255504A US7645738B2 US 7645738 B2 US7645738 B2 US 7645738B2 US 58255504 A US58255504 A US 58255504A US 7645738 B2 US7645738 B2 US 7645738B2
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methyl
lactyl
isoleucyl
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cyclo
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US20080026990A1 (en
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Peter Jeschke
Achim Harder
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Bayer Intellectual Property GmbH
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Bayer Animal Health GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to cyclic depsipeptides, in particular 18-membered cyclohexadepsipeptides, to a process for their preparation and to their use for controlling endoparasites.
  • cyclodepsipeptides having 18 ring atoms are already known as agents for controlling endoparasites (cf., for example, DE 4 317 458 A1, EP 669 343 A1, EP 658 551 A1).
  • the present invention provides novel cyclic depsipeptides and processes for preparing the cyclic depsipeptides having amino acids and hydroxycarboxylic acids as ring building blocks and 18 ring atoms.
  • the invention also provides the use of cyclic depsipeptides comprising amino acids and hydroxycarboxylic acids as ring building blocks and 18 ring atoms as agents for controlling endoparasites.
  • the present invention relates in particular to:
  • R′ represents nitrobenzyl or R′R′′N-benzyl
  • R 2 , R 3 and R 4 independently of one another represent C 1 -C 4 -alkyl
  • R 1 , R 2 , R 3 and R 4 are as defined under item 1
  • R 2 , R 3 and R 4 are as defined under item 1
  • R 2 , R 3 and R 4 are as defined under item 1
  • R 2 , R 3 and R 4 are as defined under item 1
  • the compounds of the general formula (I) can be present as geometrical and/or optical isomer mixtures of varying compositions.
  • the invention relates both to the pure isomers and to isomer mixtures.
  • R 1 represent nitrobenzyl or R′R′′N-benzyl
  • cyclic depsipeptides comprising amino acids and hydroxycarboxylic acids as ring building blocks and 18 ring atoms of the general formula (I) and salts thereof
  • cyclic depsipeptides according to the invention and their acid addition salts and metal salt complexes have good endoparasiticidal, in particular anthelmintic, action and can preferably be used in the field of veterinary medicine.
  • cyclic depsipeptides of the general formula (I) according to the invention and salts thereof contain one or more centres of chirality and may therefore be present as pure stereoisomers or in the form of various mixtures of enantiomers and diastereomers which, if required, may be separated in a manner known per se or else may be prepared by stereoselective reactions in combination with the use of stereochemically pure starting materials.
  • the invention therefore provides the pure enantiomers and diastereomers and also mixtures thereof for controlling endoparasites, in particular in the fields of medicine and veterinary medicine.
  • Suitable salts of the depsipeptides of the general formula (I) include conventional non-toxic salts, i.e. salts with appropriate bases and salts with added acids.
  • salts with inorganic bases such as alkali metal salts, for example sodium salts, potassium salts or caesium salts, alkaline earth metal salts, for example calcium salts or magnesium salts, ammonium salts, salts with organic bases and also with inorganic amines, for example triethylammonium salts, dicyclohexylammonium salts, N,N′-dibenzylethylenediammonium salts, pyridinium salts, picolinium salts or ethanolammonium salts, salts with inorganic acids, for example hydrochlorides, hydrobromides, dihydrosulphates, trihydrosulphates, or phosphates, salts with organic carboxylic acids or organic sulphonic acids, for example formates, acetates
  • the salts of the depsipeptides furthermore also include metal salt complexes, for example alkali metal salts, such as sodium salts, potassium salts or caesium salts, or alkaline earth metal salts, such as, for example, calcium salts or magnesium salts.
  • alkali metal salts such as sodium salts, potassium salts or caesium salts
  • alkaline earth metal salts such as, for example, calcium salts or magnesium salts.
  • the depsipeptides or salts thereof may also be present in the form of solvates, in particular hydrates. These are also embraced by the invention.
  • the optionally substituted radicals of the general formulae may carry one or more, preferably 1 to 3, in particular 1 to 2, identical or different substituents.
  • the following substituents may be mentioned by way of example and by way of preference:
  • the compounds of the general formula (I) are novel; they can be prepared, for example, by the process given above.
  • the cyclic depsipeptide cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-phenyllactyl-N-methyl-L-isoleucyl-D-lactyl-) and fuming nitric acid are used for nitration as compound of the general formula (II) and as nitrating agent, respectively, a mixture of cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-2-nitro-phenyllactyl-N-methyl-L-isoleucyl-D-lactyl-), cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-3-nitro-phenyllactyl-N-methyl-L-isoleucyl-D-l
  • R 1 to R 4 preferably represent those radicals which have already been mentioned in connection with the description of the compounds of the formula (I) according to the invention as being preferred for these substituents.
  • cyclic depsipeptides used as starting materials are known, and they can be prepared by total synthesis using methods known from the literature (DE 4317458 A1, EP 658551 A1).
  • cyclic depsipeptides of the general formula (II) used as starting materials can be obtained, for example, by cyclization of corresponding open-chain hexadepsipeptides (for example DE 4317458, EP 658551 A1; Jeschke et al. Bioorg. Chem. 1999, pp. 207-214) which can be prepared, for example, by methods known from the literature (for example JP 07196486 A2; open-chain tetradepsipeptides: JP 07196487 A2) (cf. Scheme 2).
  • Suitable coupling agents for cyclizing the open-chain hexadepsipeptides are all those which are suitable for generating an amide bond (cf., for example, Houben-Weyl, Methoden der Organischen Chemie, Volume 15/2; Bodansky et al., Peptide Synthesis 2nd ed. (Wiley & Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis, Synthesis, Biology (Academic Press, New York 1979)).
  • phosphonium reagents such as bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), benzotriazol-1-yl-oxy-tris(dimethylaminophosphonium) hexafluorophosphate (BOP), benzotriazol-1-yl-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP®), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBroP®), and phosphonic acid reagents, such as diethyl cyanophosphonate (DEPC) or diphenylphosphoryl azide (DPPA).
  • BOP-Cl bis(2-oxo-3-oxazolidinyl)-phosphinic chloride
  • BOP benzotriazol-1-yl-oxy-tris(dimethylaminophosphonium) hexafluorophosphate
  • Basic reaction auxiliaries suitable for carrying out the cyclization of open-chain hexadepsipeptides are all suitable basic reaction auxiliaries, such as amines, in particular tertiary amines, and alkali metal and alkaline earth metal compounds.
  • hydroxides, oxides and carbonates of lithium, sodium, potassium, magnesium, calcium and barium furthermore further basic compounds, such as amidine bases or guanidine bases, such as 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), diazabicyclo[4.3.0]nonene (DBN), diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undecene (DBU), cyclohexyltetrabutylguanidine (CyTBG), cyclohexyltetramethylguanidine (CyTMG), N,N,N,N-tetramethyl-1,8-naphthalenediamine, pentamethylpiperidine, tertiary amines, such as triethylamine, trimethylamine, tribenzylamine, triisopropylamine, tributylamine, tricyclo
  • tertiary amines in particular trialkylamines, such as triethylamine, N,N-diisopropylethylamine, N-propyldiisopropylamine, N,N′-dimethyl cyclohexylamine or N-methylmorpholine.
  • Nitrations can be carried out by customary processes as described, for example, in Houben-Weyl, Methoden der Organischen Chemie, Volume XI/2 (Georg Thieme Verlag Stuttgart 1958), pp. 99-116.
  • Nitrating agents which may be mentioned are fuming or 100% pure nitric acid (for the preparation of anhydrous nitric acid, cf. F. D. Chattaway, Soc. 1910, 97, p. 2100), if appropriate in the presence of sulphuric acid (M. J. Middleton et al., J. Heterocyclic Chem. 1970, 7, pp. 1045-1049; L. W. Deady et al. Aust. J. Chem. 1982, 35 (10), pp. 2025-2034; EP 0 192 060), or the use of nitric esters, acyl nitrate or nitronium tetrafluoroborate.
  • the nitrating agents preferably used for carrying out the process 2a according to the invention are fuming or 98-100% pure nitric acid.
  • the nitration according to process 2a is carried out by reacting the depsipeptides of the general formula (II) in the presence of a suitable nitrating agent, for example fuming nitric acid.
  • a suitable nitrating agent for example fuming nitric acid.
  • the reaction time is from 5 minutes to 72 hours.
  • the reaction is carried out at temperatures between ⁇ 50° C. and 50° C., preferably between ⁇ 30° C. and 30° C., particularly preferably at temperatures between ⁇ 15° C. and 15° C.
  • the reaction can be carried out under atmospheric pressure.
  • the operations are preferably carried out at atmospheric pressure or at pressures of up to 15 bar, and, if appropriate, under an atmosphere of protective gas (nitrogen or helium).
  • nitrating agent for carrying out the process 2a according to the invention, 5 to 10 ml, preferably 6 to ml, of nitrating agent are used per mmole of depsipeptide to be nitrated.
  • the entire reaction batch is neutralized, diluted and extracted with a suitable organic solvent, for example ethyl acetate. After separation of the organic solvent and concentration under reduced pressure, the resulting products can be purified in a customary manner by recrystallization, vacuum distillation or column chromatography (cf. Preparation Examples).
  • a suitable organic solvent for example ethyl acetate.
  • R 1 to R 4 preferably represent those radicals which have already been mentioned in connection with the description of the compounds of the formula (I) according to the invention as being preferred for these substituents.
  • Catalysts suitable for carrying out the catalytic hydrogenation are all customary hydrogenation catalysts, such as, for example, platinum catalysts (platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example palladium sponge, palladium black, palladium oxide, palladium/carbon, colloidal palladium, palladium/barium sulphate, palladium/barium carbonate, palladium hydroxide, etc.), ruthenium catalysts, cobalt catalysts (for example reduced cobalt, Raney cobalt, etc.), copper catalysts, (for example reduced copper, Raney copper, Ullman copper, etc.).
  • noble metal catalysts such as, for example, platinum and palladium or ruthenium catalysts, if appropriate on a suitable support, such as, for example, on carbon or silicon.
  • Preferred hydrogenation catalysts are palladium catalysts, in particular palladium/carbon or palladium hydroxide/carbon.
  • diluents are advantageously used in such an amount that the reaction mixture remains easily stirrable during the entire process.
  • Suitable diluents for carrying out the process according to the invention are all inert solvents.
  • halogenated hydrocarbons in particular chlorinated hydrocarbons, such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, trichlorobenzene; alcohols, such as methanol, ethanol, isopropanol, butanol; ethers, such as ethyl propyl ether, methyl tert-butyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dipropyl
  • cymene benzine fractions within a boiling point range from 70° C. to 190° C., cyclohexane, methyl cyclohexane, petroleum ether, ligroin, octane, benzene, toluene, chlorobenzene, bromobenzene, nitrotoluene, xylene; esters, such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, and dimethyl carbonate, dibutyl carbonate, ethylene carbonate; amides, such as hexamethylenephosphoric triamide, formamide, N-methyl-formamide, N,N-dimethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N-methyl-pyrrolidine, N-methyl-caprolactam, 1,3-dimethyl-3,4,5,6-tetrahydro
  • the diluents to be used depend on the reducing agent employed in each case.
  • alcohols such as, for example, methanol or ethanol, are preferred diluents for the reduction.
  • cyclic depsipeptides used as starting materials are known and can be obtained according to process 2a by nitration.
  • the reduction according to process 2b is carried out by reacting the depsipeptides of the general formula (III) in the presence of a suitable reducing agent, for example hydrogen in the presence of the catalyst palladium hydroxide/carbon.
  • a suitable reducing agent for example hydrogen in the presence of the catalyst palladium hydroxide/carbon.
  • the reaction time is from 10 minutes to 72 hours.
  • the reaction is carried out at temperatures between ⁇ 20° C. and 50° C., preferably between 10° C. and 30° C., particularly preferably at temperatures between ⁇ 5° C. and 10° C.
  • the reaction can be carried out under atmospheric pressure.
  • the operations are carried out at atmospheric pressure or at pressures of up to 15 bar and, if appropriate, under an atmosphere of protective gas (nitrogen or helium).
  • reducing agent preferably from 0.05 to 1.5 g of reducing agent are employed per mmole of depsipeptide to be reduced.
  • the reducing agent is removed and the entire reaction batch is concentrated under reduced pressure.
  • the resulting products can be purified in a customary manner by recrystallization, vacuum distillation or column chromatography (cf. Preparation Examples).
  • the pure cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-4-amino-phenyl-lactyl-N-methyl-L-isoleucyl-D-lactyl-) is used as compounds of the general formula (III) and a suitable dialdehyde, for example HOC—CH 2 —O—CH 2 —CHO generated in situ, is used as aldehyde for the aminoalkylation, cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-4-morpholino-phenyl-lactyl-N-methyl-L-isoleucyl-D-lactyl-) is formed (cf. Scheme 4).
  • R 1 to R 4 preferably represent those radicals which have already been mentioned in connection with the description of the compounds of the formula (I) according to the invention as being preferred for these substituents.
  • the cyclic depsipeptides used as starting materials can be obtained by process 2b.
  • the dialdehyde used as starting material can be obtained by processes known from the literature, for example (i) by sodium periodate oxidation from 1,4-anhydro-meso-erythritol (E. M. Acton et al. J. Med. Chem. 1984, 27, pp. 638-645), (ii) by hydrolysis of the diketal (RO) 2 —CH 2 —O—CH 2 —(O—R) 2 in the presence of 50% strength acetic acid (F. J. Lopez Aparicio et al. Carbohydrat Res. 1982, 111 (1), pp.
  • Suitable for hydrogenation of the azomethynes formed in situ are, for example, various hydrogenating agents, such as, for example, alkali metal hydrides, in particular sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaCNBH 3 ), lithium aluminium hydride (LiAlH 4 ), lithium triethylborohydride (Li[Et 3 BH]), lithium tri-sec-borohydride (Li[sec-Bu 3 BH]), sodium-bis(2-methoxyethoxy)-aluminium hydride, alkylaluminium hydrides, in particular diisobutylaluminium hydride (DIBAL-H) or tetramethylammoniumtriacetoxy borohydride, inter alia (cf. H. de Koning, W. N. Speckamp, Houben Weyl E 21, p. 1953 and literature cited therein).
  • alkali metal hydrides in particular sodium borohydride (Na
  • borohydride resin for example “borohydride on Amberlite® IRA-406”, for the hydrogenation (cf. Sande A. R. et al., Tetrahedron Lett. 1984, 25, p. 3501).
  • alkali metal hydrides in particular sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaCNBH 3 ), lithium aluminium hydride (LiAlH 4 ).
  • the reductive alkylation according to process 2b is carried out by reacting the depsipeptides of the general formula (III) in the presence of a diluent and in the presence of an aldehyde and a suitable reducing agent, for example sodium cyanoborohydride.
  • a suitable reducing agent for example sodium cyanoborohydride.
  • the reaction time is from 10 minutes to 72 hours.
  • the reaction is carried out at temperatures between ⁇ 20° C. and 50° C., preferably between ⁇ 10° C. and 30° C., particularly preferably at temperatures between ⁇ 5° C. and 10° C.
  • the reaction can be carried out under atmospheric pressure.
  • the operations are preferably carried out at atmospheric pressure or at pressures of up to 15 bar and, if appropriate, under an atmosphere of protective gas (nitrogen or helium).
  • the entire reaction batch is neutralized, diluted and extracted with an organic solvent, for example a chlorinated hydrocarbon.
  • an organic solvent for example a chlorinated hydrocarbon.
  • the resulting products can be purified in a customary manner by recrystallization, vacuum distillation or column chromatography (cf. Preparation Examples).
  • the pure cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-4-amino-phenyl-lactyl-N-methyl-L-isoleucyl-D-lactyl-) is used as compounds of the general formula (III) and a dialdehyde, for example HOC—CH 2 —SO 2 —CH 2 —CHO, is used as aldehyde for the aminoalkylation, surprisingly and according to the invention, cyclo(-N-methyl-L-alanyl-D-lactyl-N-methyl-L-isoleucyl-D-4-(2-hydroxyethylsulphonyl-ethylamino-phenyl)lactyl-N-methyl-L-isoleucyl-D-lactyl-) is formed (cf. Scheme 6).
  • R 1 to R 4 preferably represent those radicals which have already been mentioned in connection with the description of the compounds of the formula (I) according to the invention as being preferred for these substituents.
  • the cyclic depsipeptides used as starting materials can be obtained according to process 2b.
  • the reductive alkylation according to process 2c is carried out by reacting the depsipeptides of the general formula (III) in the presence of a solvent and in the presence of an aldehyde and a suitable reducing agent, for example sodium cyanoborohydride.
  • a suitable reducing agent for example sodium cyanoborohydride.
  • the reaction time is from 10 minutes to 72 hours.
  • the reaction is carried out at temperatures between ⁇ 20° C. and 50° C., preferably between ⁇ 10° C. and 30° C., particularly preferably at temperatures between ⁇ 5° C. and 10° C.
  • the reaction can be carried out under atmospheric pressure.
  • the operations are preferably carried out at atmospheric pressure or at pressures of up to 15 bar and, if appropriate, under an atmosphere of protective gas (nitrogen or helium).
  • the entire reaction batch is neutralized, diluted and extracted with an organic solvent, for example a chlorinated hydrocarbon.
  • an organic solvent for example a chlorinated hydrocarbon.
  • the resulting products can be purified in a customary manner by recrystallization, vacuum distillation or column chromatography (cf. Preparation Examples).
  • the cyclization can also be carried out by reacting the compounds of the general formula (IV) with compounds of the general formula (V), if appropriate in the presence of one of the basic reaction auxiliaries mentioned further above: E—CHR′ 1 —CHR′ 2 —X—CHR′ 3 —CHR′ 4 —E (V)
  • X preferably represents oxygen, sulphur, sulphonyl or optionally substituted amino
  • the radicals R′1-R′4 preferably represent C 1 -C 2 -alkyl, for example methyl or ethyl
  • E preferably represents a suitable leaving group, for example halogen, in particular fluorine, chlorine, bromine or iodine, methylsulphonyloxy (Ms-O) or para-toluenesulphonyloxy (p-Tos-O).
  • the compounds of the general formula (V) are known from the literature and their use, for example for cyclizations, has been described (cf. WO 93/10053).
  • the alkylation is carried out, for example, by reacting the depsipeptides of the general formula (III) in the presence of a solvent and in the presence of a basic reaction auxiliary, according to Scheme 7.
  • inert solvents in each case solvents which are inert under the respective reaction conditions, but which do not have to be inert under all conceivable reaction conditions.
  • the active compounds are suitable for controlling pathogenic endoparasites encountered in humans and in animal husbandry and livestock breeding, in productive livestock, breeding stock, zoo animals, laboratory animals, animals used in experiments, and pets, and have low toxicity towards warm-blooded animals. Preference is given to application on endoparasites of warm-blooded animals, in particular mammals. They are active against resistant and normally sensitive species and against all or some stages of development of the pests. By controlling the pathogenic endoparasites, it is intended to reduce disease, mortality and decreasing performance (for example in the production of meat, milk, wool, hides, eggs, honey, etc.), so that more economical and simpler animal keeping is possible by using the active compounds.
  • the pathogenic endoparasites include Cestodes, Trematodes, Nematodes, in particular:
  • Cyclophyllidea for example Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplopylidium spp.
  • Oxyurida From the order of the Oxyurida, for example Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
  • Ascaridia From the order of the Ascaridia, for example Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
  • the livestock and breeding stock include mammals, such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, such as, for example, minks, chinchilla or racoon, birds, such as, for example chickens, geese, turkeys or ducks, freshwater fish and sea fish, such as, for example, trout, carp and eels, reptiles and insects, such as, for example, honey bee and silkworm.
  • mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, such as, for example, minks, chinchilla or racoon
  • birds such as, for example chickens, geese, turkeys or ducks, freshwater fish and sea fish, such as, for example, trout, carp and
  • the laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • the pets include dogs and cats.
  • Administration can be effected prophylactically as well as therapeutically.
  • the active substances are administered, either directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally, by treating the habitat or with the aid of shaped articles containing the active compound, such as, for example, strips, plates, tapes, collars, ear tags, limb bands or marking devices.
  • Enteral administration of the active compounds is effected for example orally in the form of powders, tablets, capsules, pastes, drinks, granules, solutions, boluses, medicated feed or drinking water.
  • Dermal application is effected, for example, in the form of dipping, spraying, bathing, washing, pouring-on and spotting-on and powdering.
  • Parenteral administration is effected, for example, in the form of injection (intramuscular, subcutaneous, intravenous or intraperitoneal) or by implants.
  • Suitable preparations include:
  • solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;
  • solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules; aerosols and inhalants, shaped articles containing the active compound.
  • Solutions for injection are administered intravenously, intramuscularly and subcutaneously.
  • Solutions for injection are prepared by dissolving the active compound in a suitable solvent and, if desired, adding additives, such as solubilizers, acids, bases, buffer salts, antioxidants, or preservatives.
  • additives such as solubilizers, acids, bases, buffer salts, antioxidants, or preservatives.
  • the solutions are sterile-filtered and decanted into containers.
  • Suitable solvents include: physiologically acceptable solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols and N-methyl-pyrrolidone, and their mixtures.
  • physiologically acceptable solvents such as water, alcohols, such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols and N-methyl-pyrrolidone, and their mixtures.
  • the active compounds can also be dissolved in physiologically acceptable vegetable or synthetic oils which are suitable for injection.
  • Suitable solubilizers include: solvents which facilitate the dissolution of the active compound in the main solvent or which prevent precipitation of the active compound.
  • solubilizers are polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.
  • benzyl alcohol trichlorobutanol
  • p-hydroxybenzoic esters or n-butanol.
  • Oral solutions are administered directly. Concentrates are first diluted to the administration concentration and then administered orally. Oral solutions and concentrates are prepared as described above in the case of the solutions for injection, sterile procedures not being necessary.
  • Solutions for use on the skin are applied drop by drop, smoothed on, rubbed in, splashed on or sprayed on or are applied by dipping (bathing or washing). These solutions are prepared as described above in the case of the solutions for injection.
  • thickeners inorganic thickeners, such as bentonites, colloidal silica, aluminium monostearate, or organic thickeners, such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
  • Gels are applied to the skin or smoothed on or introduced into body cavities. Gels are prepared by adding such an amount of thickener to solutions which have been prepared as described for the solutions for injection that a clear composition is formed which has an ointment-like consistency.
  • the thickeners used are the thickeners indicated further above.
  • Pour-on and spot-on formulations are poured or splashed onto limited areas of the skin, the active compound penetrating the skin and acting systemically or being distributed on the body surface.
  • pour-on and spot-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable solvents or solvent mixtures which are tolerated by the skin. If appropriate, other auxiliaries, such as colorants, absorption promoters, antioxidants, photostabilizers or tackifiers are added.
  • Suitable solvents include: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols, such as benzyl alcohol, phenylethanol or phenoxyethanol, esters, such as ethyl acetate, butyl acetate or benzyl benzoate, ethers, such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether or diethylene glycol mono-butyl ether, ketones, such as acetone or methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl-acetamide, N-methylpyrrolidone, or 2,2-dimethyl-4-oxy-methylene-1,3-dioxolane.
  • aromatic alcohols such as benzyl alcohol, phenylethanol or phenoxyethanol
  • esters such as ethyl acetate, butyl
  • Colorants are all colorants which can be dissolved or suspended and which are approved for use in animals.
  • absorption promoters examples include DMSO, spreading oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides or fatty alcohols.
  • antioxidants sulphites or metabisulphites, such as potassium metabisulphite, ascorbic acid, butylhydroxytoluene, butylhydroxyanisole or tocopherol.
  • photostabilizers are compounds from the class of the benzophenones and novantisolic acid.
  • Tackifiers are, for example, cellulose derivatives, starch derivatives, polyacrylates or natural polymers such as alginates or gelatine.
  • Emulsions can be administered orally, dermally or as injections.
  • Emulsions are either the water-in-oil type or the oil-in-water type.
  • They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and by homogenizing this phase with the solvent of the other phase, with the aid of suitable emulsifiers and, if appropriate, other auxiliaries, such as colorants, absorption promoters, preservatives, antioxidants, photostabilizers, and viscosity-increasing substances.
  • Suitable hydrophobic phases include: paraffin oils, silicone oils, natural vegetable oils such as sesame seed oil, almond oil or castor oil, synthetic triglycerides, such as caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty acids of chain length C 8-12 or other specifically selected natural fatty acids, mixtures of partial glycerides of saturated or unsaturated fatty acids which may also contain hydroxyl groups, and mono- and diglycerides of the C 8 /C 10 -fatty acids.
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid having a medium chain length with saturated fatty alcohols of chain length C 16 -C 18 , isopropyl myristate, isopropyl palmitate, caprylic/capric esters of saturated fatty alcohols of chain length C 12 -C 18 , isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, waxy fatty acid esters such as artificial duck uropygial fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, etc.
  • esters such as ethyl stearate, di-n-butyryl adipate, hex
  • Fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol.
  • Fatty acids such as, for example, oleic acid and its mixtures.
  • Suitable hydrophilic phases include:
  • alcohols such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.
  • Suitable emulsifiers include: nonionic surfactants, for example polyethoxylated castor oil, polyethoxylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate or alkylphenol polyglycol ethers;
  • ampholytic surfactants such as disodium N-lauryl- ⁇ -iminodipropionate or lecithin;
  • anionic surfactants such as Na lauryl sulphate, fatty alcohol ether sulphates, and the monoethanolamine salt of mono/dialkylpolyglycol ether orthophosphoric ester;
  • cationic surfactants such as cetyltrimethylammonium chloride.
  • Suitable other auxiliaries include: substances which increase the viscosity and stabilize the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, methylvinyl ether/maleic anhydride copolymers, polyethylene glycols, waxes, colloidal silica, or mixtures of the listed substances.
  • substances which increase the viscosity and stabilize the emulsion such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatine, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, methylvinyl ether/maleic anhydride copolymers, polyethylene glycols, waxes, colloidal silica, or mixtures of the listed substances.
  • Suspensions can be administered orally, dermally or as an injection. They are prepared by suspending the active compound in a liquid excipient, if appropriate with the addition of other auxiliaries, such as wetting agents, colorants, absorption promoters, preservatives, antioxidants and photostabilizers.
  • auxiliaries such as wetting agents, colorants, absorption promoters, preservatives, antioxidants and photostabilizers.
  • Suitable liquid excipients include all homogeneous solvents and solvent mixtures.
  • Suitable wetting agents include the surfactants indicated further above.
  • Suitable other auxiliaries include those indicated further above.
  • Semi-solid preparations can be administered orally or dermally. They are only distinguished from the above-described suspensions and emulsions by their higher viscosity.
  • the active compound is mixed with suitable excipients, if appropriate with the addition of auxiliaries, and the mixture is formulated as desired.
  • Suitable excipients include all physiologically acceptable solid inert substances. Suitable for this purpose are inorganic and organic substances. Inorganic substances are, for example, common salt, carbonates, such as calcium carbonate, hydrogen carbonates, aluminium oxides, silicas, clays, precipitated or colloidal silica, and phosphates.
  • Organic substances are, for example, sugars, cellulose, foodstuffs and animal feeds, such as powdered milk, animal meals, cereal meals, coarse cereal meals and starches.
  • Auxiliaries are preservatives, antioxidants and colorants which have already been mentioned further above.
  • auxiliaries are lubricants and glidants, such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants, such as starch or crosslinked polyvinylpyrrolidone, binders, such as, for example, starch, gelatine or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.
  • lubricants and glidants such as, for example, magnesium stearate, stearic acid, talc, bentonites, disintegrants, such as starch or crosslinked polyvinylpyrrolidone, binders, such as, for example, starch, gelatine or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose.
  • the active compound according to the invention in its preparations and in the use forms prepared from these preparations, may be present as a mixture with other active compounds such as insecticides, sterilants, bactericides, acaricides, nematicides or fungicides.
  • the insecticides include, for example, phosphoric esters, carbamates, carboxylic esters, chlorinated hydrocarbons, phenylureas, nicotinyls, neonicotinyls, substances produced by microorganisms and the like.
  • bronopol dichlorophen, nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone, furancarboxylic acid, oxytetracyclin, probenazole, streptomycin, tecloftalam, copper sulphate and other copper preparations, quinolones, such as ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, flumequine, ibafloxacin, marbofloxacin, norfloxacin, ofloxacin, orbifloxacin, premafloxacin, sarafloxacin.
  • the active compounds according to the invention may be present, in their commercially available formulations and in the use forms prepared from these formulations, as a mixture with synergists.
  • Synergists are compounds by which the action of the active compounds is increased without it being necessary for the synergist added to be active itself.
  • Ready-to-use preparations comprise the active compound in concentrations of from 10 ppm to 20% by weight, preferably from 0.1 to 10% by weight.
  • Preparations which are diluted prior to use comprise the active compound in concentrations of from 0.5 to 90% by weight, preferably from 5 to 50% by weight.
  • ozone gas is introduced into a mixture of 103 mg (1.47 mmol) of 2,5-dihydrofuran, 0.8 ml of methanol and 3.1 ml of dichloromethane until the reaction mixture has a bluish colour (olefin consumption). Excess ozone is then flushed out in a stream of argon (which is passed through potassium iodide). 185 mg (2.94 mmol) of sodium cyanoborohydride are added to the solution, and the reaction mixture is stirred at ⁇ 50° C. for 10 minutes.
  • ozone gas is introduced into a mixture of 80.16 mg (0.67 mmol) of 3-sulpholene, 0.36 ml of methanol and 1.44 ml of dichloromethane until the reaction mixture has a bluish colour (olefin consumption). Excess ozone is then flushed out in a stream of argon (which is passed through potassium iodide). 82.26 mg (1.36 mmol) of sodium cyanoborohydride are added to the solution, and the reaction mixture is stirred at ⁇ 50° C. for 10 minutes.
  • Single crystals suitable for X-ray analysis can be obtained by recrystallization from a chloroform/n-hexane solvent mixture.
  • the latice constant and the reflex intensities were determined at ⁇ 80° C. in a Siemens P4 four-circle diffractometer.
  • the structure was resolved using direct methods (programme system SHELXTL). The following structure was determined using the programme SHELXL-93 against F 2 .
  • BOP-CI bis(2-oxo-3-oxazolidinyl)phosphonium chloride
  • the degree of effectiveness is determined by quantitatively counting the worm eggs which have been excreted with the faeces before and after the treatment.
  • a complete cessation of egg excretion after the treatment means that the worms have been aborted or damaged to such an extent that they no longer produce eggs (dosis effectiva).
  • the degree of effectiveness is determined by quantitatively counting the worm eggs which have been excreted with the faeces before and after the treatment.
  • a complete cessation of egg excretion after the treatment means that the worms have been aborted or damaged to such an extent that they no longer produce eggs (dosis effectiva).

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US10/582,555 2003-12-19 2004-12-07 18-membered nitrobenzyl- and aminobenzyl-substituted cyclohexadepsipeptides for controlling endoparasites and a process for their preparation Expired - Fee Related US7645738B2 (en)

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DE10359798A DE10359798A1 (de) 2003-12-19 2003-12-19 Cyclohexadepsipeptide zur Bekämpfung von Endoparasiten und ein Verfahren zu ihrer Herstellung
PCT/EP2004/013896 WO2005063277A1 (de) 2003-12-19 2004-12-07 18 gliedrige nitrobenzyl-und aminobenzyl-substituierte cyclohexadepsipeptide zur bekämpfung von endoparasiten und ein verfahren zu ihrer herstellung

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WO1995027498A1 (de) 1994-04-12 1995-10-19 Bayer Aktiengesellschaft Verwendung von cyclischen depsipeptiden mit 18 ringatomen
WO1996038165A2 (de) 1995-06-02 1996-12-05 Bayer Aktiengesellschaft Endoparasitizide mittel
US5589503A (en) * 1994-01-11 1996-12-31 Bayer Aktiengesellschaft Endoparasiticidal compositions
EP0664297B1 (de) 1994-01-19 1998-04-08 Bayer Ag Verwendung von cyclischen Depsipeptiden mit 12 Ringatomen zur Bekämpfung von Endoparasiten, neue cyclische Depsipeptide mit 12 Ringatomen und Verfahren zu ihrer Herstellung

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DE4406025A1 (de) * 1994-02-24 1995-08-31 Bayer Ag Milchsäure-haltige cyclische Depsipeptide mit 18 Ringatomen als endoparasitizide Mittel und Verfahren zu ihrer Herstellung
CN1076349C (zh) * 1997-06-04 2001-12-19 拜尔公司 去氧环缩肽及其防治体内寄生虫的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589503A (en) * 1994-01-11 1996-12-31 Bayer Aktiengesellschaft Endoparasiticidal compositions
EP0662326B1 (de) 1994-01-11 2001-11-28 Bayer Ag Endoparasitizide Mittel die Praziquantel und Epsiprantel enthalten
EP0664297B1 (de) 1994-01-19 1998-04-08 Bayer Ag Verwendung von cyclischen Depsipeptiden mit 12 Ringatomen zur Bekämpfung von Endoparasiten, neue cyclische Depsipeptide mit 12 Ringatomen und Verfahren zu ihrer Herstellung
WO1995027498A1 (de) 1994-04-12 1995-10-19 Bayer Aktiengesellschaft Verwendung von cyclischen depsipeptiden mit 18 ringatomen
WO1996038165A2 (de) 1995-06-02 1996-12-05 Bayer Aktiengesellschaft Endoparasitizide mittel

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DE502004009401D1 (de) 2009-06-04
JP5196788B2 (ja) 2013-05-15
MXPA06006662A (es) 2006-08-31
ES2323531T3 (es) 2009-07-20
AU2004308593A1 (en) 2005-07-14
AU2004308593B2 (en) 2011-11-10
US20080026990A1 (en) 2008-01-31
CA2550344A1 (en) 2005-07-14
EP1715883B1 (de) 2009-04-22
DE10359798A1 (de) 2005-07-21
WO2005063277A1 (de) 2005-07-14
ATE429239T1 (de) 2009-05-15
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